scholarly journals Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration

2019 ◽  
Author(s):  
Andrea Loreto ◽  
Ciaran S. Hill ◽  
Victoria L. Hewitt ◽  
Giuseppe Orsomando ◽  
Carlo Angeletti ◽  
...  
Keyword(s):  
Wallerian Degeneration ◽  
Sympathetic Neurons ◽  
Axon Degeneration ◽  
Loss Of Function ◽  
Mitochondrial Uncoupling ◽  
Charcot Marie Tooth Disease ◽  
Mitochondrial Impairment ◽  
Metabolic Fingerprint ◽  
Mitochondrial Defects ◽  
Tooth Disease

ABSTRACTWallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson’s disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders.

scholarly journals Axonal Transport Defects in a Mitofusin 2 Loss of Function Model of Charcot-Marie-Tooth Disease in Zebrafish

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e67276 ◽  
Author(s):  
Anna L. Chapman ◽  
Ellen J. Bennett ◽  
Tennore M. Ramesh ◽  
Kurt J. De Vos ◽  
Andrew J. Grierson
Keyword(s):  
Axonal Transport ◽  
Loss Of Function ◽  
Function Model ◽  
Mitofusin 2 ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

scholarly journals SIRT2-knockdown Rescues GARS-induced Charcot-Marie-Tooth Neuropathy

2019 ◽  
Author(s):  
Chao Shen ◽  
Qian Qi ◽  
Yicai Qin ◽  
Dejian Zhou ◽  
Xinyuan Chen ◽  
...  
Keyword(s):  
Trna Synthetase ◽  
Nerve Degeneration ◽  
Loss Of Function ◽  
Wild Type ◽  
Partial Loss ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Underlying Mechanisms ◽  
Tooth Disease

AbstractCharcot-Marie-Tooth disease is the most common inherited peripheral neuropathy. Dominant mutations in glycyl-tRNA synthetase (GARS) gene cause peripheral nerve degeneration and lead to CMT disease type 2D. Mutations in GARS (GARSCMT2D) show partial loss-of-function features, suggesting that tRNA-charging deficits play a role in disease pathogenesis, but the underlying mechanisms are not fully understood. In this study we report that wild-type GARS tightly binds the NAD+-dependent deacetylase SIRT2 and inhibits its deacetylation activity, resulting in the hyperacetylated α-tubulin, the major substrate of SIRT2. Previous studies showed that acetylation of α-tubulin protects microtubules from mechanical breakage and keep axonal transportation. However, CMT2D mutations in GARS can not inhibit SIRT2 deacetylation, which leads to decrease acetylated α-tubulin and severe axonal transport deficits. Genetic reduction of SIRT2 in the Drosophila model rescues the GARS–induced axonal CMT neuropathy and extends the life span. Our findings demonstrate the pathogenic role of SIRT2-dependent α-tubulin deacetylation in mutant GARS-induced neuropathies and provide new perspectives for targeting SIRT2 as a potential therapy against hereditary axonopathies.

scholarly journals Connexin32 Mutations Associated with X-Linked Charcot–Marie–Tooth Disease Show Two Distinct Behaviors: Loss of Function and Altered Gating Properties

1998 ◽  
Vol 18 (11) ◽  
pp. 4063-4075 ◽  
Author(s):  
Catherine Ressot ◽  
Danielle Gomès ◽  
André Dautigny ◽  
Danielle Pham-Dinh ◽  
Roberto Bruzzone
Keyword(s):  
Loss Of Function ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

scholarly journals Fly model causes neurological rethink

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Madhumala K Sadanandappa ◽  
Mani Ramaswami
Keyword(s):  
Neurological Disorder ◽  
Therapeutic Approach ◽  
Loss Of Function ◽  
Partial Loss ◽  
Gain Of Function ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Drosophila Model ◽  
Tooth Disease

A Drosophila model for a neurological disorder called type 2B Charcot-Marie-Tooth disease reveals that it has its origins in a partial loss of function, rather than a gain of function, which points to the need for a new therapeutic approach.

scholarly journals Smaug1 membrane-less organelles respond to AMPK/mTOR and affect mitochondrial function‡

2021 ◽  
Author(s):  
Ana J. Fernández-Alvarez ◽  
María Gabriela Thomas ◽  
Malena L. Pascual ◽  
Martín Habif ◽  
Jerónimo Pimentel ◽  
...  
Keyword(s):  
Single Molecule ◽  
Mitochondrial Respiration ◽  
Rna Binding ◽  
Cell Types ◽  
Mitochondrial Enzymes ◽  
Mitochondrial Network ◽  
Loss Of Function ◽  
Mitochondrial Complex ◽  
Mitochondrial Uncoupling ◽  
Mitochondrial Defects

Smaug is a conserved translational regulator that binds numerous mRNAs, including nuclear transcripts that encode mitochondrial enzymes. Smaug orthologs form cytosolic membrane-less organelles (MLOs) in several organisms and cell types. We have performed single-molecule FISH assays that revealed that SDHB and UQCRC1 mRNAs associate with Smaug1 bodies in U2OS cells. Loss of function of Smaug1 and Smaug2 affected both mitochondrial respiration and morphology of the mitochondrial network. Phenotype rescue by Smaug1 transfection depends on the presence of its RNA binding domain. Moreover, we identified specific Smaug1 domains involved in MLO formation, and found that impaired Smaug1 MLO condensation correlates with mitochondrial defects. Mitochondrial Complex I inhibition by rotenone –but not strong mitochondrial uncoupling by CCCP– rapidly induced Smaug1 MLOs dissolution. Metformin and rapamycin elicited similar effects, which were blocked by pharmacological inhibition of AMPK. Finally, we found that Smaug1 MLO dissolution weakens the interaction with target mRNAs, thus enabling their release. We propose that mitochondrial respiration and the AMPK/mTOR balance controls the condensation and dissolution of Smaug1 MLOs, thus regulating nuclear mRNAs that encode key mitochondrial proteins.

scholarly journals A dysfunctional endolysosomal pathway common to two sub-types of demyelinating Charcot–Marie–Tooth disease

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
James R. Edgar ◽  
Anita K. Ho ◽  
Matilde Laurá ◽  
Rita Horvath ◽  
Mary M. Reilly ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Human Fibroblasts ◽  
Cell Types ◽  
Loss Of Function ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Recessive Mutations ◽  
Late Endosomes ◽  
Demyelinating Peripheral Neuropathy ◽  
Tooth Disease

Abstract Autosomal dominant mutations in LITAF are responsible for the rare demyelinating peripheral neuropathy, Charcot–Marie–Tooth disease type 1C (CMT1C). The LITAF protein is expressed in many human cell types and we have investigated the consequences of two different LITAF mutations in primary fibroblasts from CMT1C patients using confocal and electron microscopy. We observed the appearance of vacuolation/enlargement of late endocytic compartments (late endosomes and lysosomes). This vacuolation was also observed after knocking out LITAF from either control human fibroblasts or from the CMT1C patient-derived cells, consistent with it being the result of loss-of-function mutations in the CMT1C fibroblasts. The vacuolation was similar to that previously observed in fibroblasts from CMT4J patients, which have autosomal recessive mutations in FIG4. The FIG4 protein is a component of a phosphoinositide kinase complex that synthesises phosphatidylinositol 3,5-bisphosphate on the limiting membrane of late endosomes. Phosphatidylinositol 3,5-bisphosphate activates the release of lysosomal Ca2+ through the cation channel TRPML1, which is required to maintain the homeostasis of endosomes and lysosomes in mammalian cells. We observed that a small molecule activator of TRPML1, ML-SA1, was able to rescue the vacuolation phenotype of LITAF knockout, FIG4 knockout and CMT1C patient fibroblasts. Our data describe the first cellular phenotype common to two different subtypes of demyelinating CMT and are consistent with LITAF and FIG4 functioning on a common endolysosomal pathway that is required to maintain the homeostasis of late endosomes and lysosomes. Although our experiments were on human fibroblasts, they have implications for our understanding of the molecular pathogenesis and approaches to therapy in two subtypes of demyelinating Charcot–Marie–Tooth disease.

scholarly journals MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A

Science ◽  
2018 ◽  
Vol 360 (6386) ◽  
pp. 336-341 ◽  
Author(s):  
Agostinho G. Rocha ◽  
Antonietta Franco ◽  
Andrzej M. Krezel ◽  
Jeanne M. Rumsey ◽  
Justin M. Alberti ◽  
...  
Keyword(s):  
Disease Type ◽  
Preclinical Models ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Mitochondrial Defects ◽  
Tooth Disease

scholarly journals A Recurrent Loss-of-Function Alanyl-tRNA Synthetase (AARS) Mutation in Patients with Charcot-Marie-Tooth Disease Type 2N (CMT2N)

2014 ◽  
Vol 35 (4) ◽  
pp. 512-512 ◽  
Author(s):  
Heather M. McLaughlin ◽  
Reiko Sakaguchi ◽  
William Giblin ◽  
Thomas E. Wilson ◽  
Leslie Biesecker ◽  
...  
Keyword(s):  
Trna Synthetase ◽  
Disease Type ◽  
Loss Of Function ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

scholarly journals A Recurrent loss-of-function alanyl-tRNA synthetase (AARS ) mutation in patients with charcot-marie-tooth disease type 2N (CMT2N)

2011 ◽  
Vol 33 (1) ◽  
pp. 244-253 ◽  
Author(s):  
Heather M. McLaughlin ◽  
Reiko Sakaguchi ◽  
William Giblin ◽  
Thomas E. Wilson ◽  
Leslie Biesecker ◽  
...  
Keyword(s):  
Trna Synthetase ◽  
Disease Type ◽  
Loss Of Function ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease
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